OP0216 THE CLINICAL AND PATHOLOGICAL ROLES OF AUTOANTIBODIES TARGETING BMP SIGNALING IN SYSTEMIC LUPUS ERYTHEMATOSUS-ASSOCIATED PULMONARY ARTERIAL HYPERTENSION
Authors: J. Qian, Y. Xing, D. Yufang, X. Deng, J. Zhao, Q. Wang, Z. Tian, M. LI, X. Zeng
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Pulmonary arterial hypertension (PAH) is one of the most severe complications and the leading cause of death in patients with systemic lupus erythematosus (SLE). Pathogenic mechanisms leading to SLE-PAH are still not fully understood. In idiopathic PAH, the dysfunction of the bone morphogenetic protein (BMP) pathway was found to be involved in pulmonary artery remodeling [1]. In SLE-PAH, our previous study identified serum autoantibodies targeting BMP receptors (BMPR) as the potential biomarker, including anti-BMPR2, BMPR1A, and Activin Receptor-Like Kinase type 1 (ALK1) antibodies [2]. However, the clinical and pathological roles of the above autoantibodies targeting BMP signaling in SLE-PAH remain uncertain. <h3>Objectives</h3> To investigate the clinical and pathological roles of autoantibodies targeting BMPR2, BMPR1A, and ALK1 in SLE-PAH. <h3>Methods</h3> Patients of SLE-PAH confirmed by right heart catheterization were enrolled and serum levels of autoantibodies targeting BMPR2, BMPR1A, and ALK1 were measured by ELISA. Patients with SLE-PAH were subtyped by cluster analysis. Survival and treatment goal achievement were further compared between different clusters. The Id1 and phospho-SMAD1/5 (p-SMAD1/5) levels were examined in human pulmonary artery endothelial cells (hPAEC) under the induction of BMP9 combined with anti-BMPR2, anti-ALK1, and anti-BMPR1A neutralizing antibodies (5 μg/mL). The effect of anti-ALK1 antibodies on the extent of monolayer permeability and apoptosis of hPAEC was further examined. <h3>Results</h3> 60 SLE-PAH patients were enrolled and cluster analysis revealed two distinct clusters according to the positivity of autoantibodies targeting BMP signaling and clinical manifestations. Cluster 1 was a "low-antibody and high-disease activity" cluster while cluster 2 was a "high-antibody and low-disease activity" cluster. Patients in cluster 1 showed a higher proportion of nephropathy (76.9%) and SLE activity, however a low positivity rate of autoantibodies targeting BMP signaling. Patients in cluster 2 were characterized by a higher rate of anti-BMPR2 antibodies (82.4%), anti-ALK antibodies (70.6%), and lower SLE activity. Prognostic analysis showed that the proportion of patients who reached the treatment target was relatively higher in cluster 2. Mechanism study showed that the p-SMAD1/5 level and the Id1expression were decreased, indicating the suppression of BMP signaling in the presence of anti-ALK1 antibodies. Functional studies showed that anti-ALK1 antibodies increased the monolayer permeability of hPAEC. The late-stage apoptosis of hPAECs was also induced by anti-ALK1 antibodies. <h3>Conclusion</h3> The serum positivity of autoantibodies targeting BMP signaling has clinical potential in dividing SLE-PAH patients into two distinct clusters. The anti-ALK1 antibodies can downregulate BMP signaling and mediate great permeability and apoptosis in hPAECs, which may be involved in the pathogenesis of SLE-PAH. <h3>References</h3> [1]Dewachter L, et.al. Eur Respir J 34 (5):1100-1110. [2]Xing Y, et.al. FASEB J 35 (12):e22044. <h3>Acknowledgements</h3> We thank CSTAR co-authors as following for assistance with cases collections. <h3>Disclosure of Interests</h3> None Declared.